ORIGINAL RESEARCH article
Front. Immunol.
Sec. Molecular Innate Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1706301
This article is part of the Research TopicDevelopment of Diagnostic and Therapeutic Biomarkers for Tumors and Inflammation Based on Multi-omics Approaches Including Transcriptomics, Proteomics, and MetabolomicsView all 12 articles
Multi-Omics Discovery of a Kbhb–SSBP1 Axis Linking Mitochondrial Homeostasis to Temozolomide Resistance in Glioblastoma
Provisionally accepted
Yongjie Chen1Yifei Xiao2
Jiangbin Ren3
Qiang Gu4
Yuanqi Chu1Ende Li1Ruisheng Ge1
Yuwen Song1
Kan Wang1*
Qinla Li5*- 1Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
- 2First Affiliated Hospital of Harbin Medical University, Harbin, China
- 3Tianjin Huanhu Hospital, Tianjin, China
- 4Fujian Provincial Cancer Hospital, Fuzhou, China
- 5The Second Hospital of Heilongjiang Province, Harbin, China
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Background: Glioblastoma (GBM) is the most lethal primary brain tumor, with limited treatment efficacy due to rapid development of temozolomide (TMZ) resistance. Lysine β-hydroxybutyrylation (Kbhb), a metabolically derived post-translational modification, has been implicated in cancer biology, but its role in GBM chemoresistance remains unclear. Methods: We integrated bulk RNA sequencing, single-cell RNA-seq, and spatial transcriptomics to identify Kbhb-related, TMZ-resistance-associated genes (Kbhb-TR genes) in GBM. A prognostic model was established and validated in independent cohorts. Immune profiling, molecular subtype analysis, and drug sensitivity prediction were performed. Functional assays and site-directed mutagenesis were used to investigate the role of SSBP1 and lysine 122-specific Kbhb modification in TMZ-resistant GBM cells. Results: We identified 136 Kbhb-TR genes and constructed a five-gene prognostic model (PARVB, ANXA2, MAPRE3, FAM169A, SSBP1) with robust survival stratification. SSBP1 was highly expressed in TMZ-resistant GBM cells and predominantly modified by Kbhb at lysine 122. Mutation of this site (K122R) abolished the modification, impaired mitochondrial membrane potential, increased ROS, and reduced TMZ resistance. Single-cell analysis revealed enrichment of Kbhb-high cells in MES-like GBM, activation of DNA repair and immunosuppressive pathways, and enhanced crosstalk with microglia and monocytes via PTN, MDK, and SPP1 signaling. Conclusion: Our study identifies a novel Kbhb-SSBP1 axis that sustains mitochondrial homeostasis and promotes TMZ resistance in GBM. Targeting Kbhb modification or SSBP1 function may represent a promising strategy to overcome chemoresistance.
Keywords: Glioblastoma, β-hydroxybutyrylation, SSBP1, temozolomide resistance, Mitochondrial function, Single-cell transcriptomics
Received: 16 Sep 2025; Accepted: 21 Oct 2025.
Copyright: © 2025 Chen, Xiao, Ren, Gu, Chu, Li, Ge, Song, Wang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Kan Wang, 2020022013@hrbmu.edu.cn
Qinla Li, babyslover@126.com
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